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ABSTRACT The association of serum N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) with insulin resistance (IR), as measured by homeostasis model assessment of insulin resistance (HOMA‐IR), in the general population is unclear. Our study aimed to characterize its relationship in a large community‐based population. Subjects were recruited from the Danyang city between 2017 and 2019. Serum NT‐proBNP was measured using an enhanced chemiluminescence immunoassay. IR was defined by a HOMA‐IR in the highest sex‐specific quartile. Categorical and continuous analyses were performed with sex‐specific NT‐proBNP tertiles and naturally logarithmically transformed NT‐proBNP (lnNTproBNP), respectively. The 2945 participants (mean age 52.8 years) included 1728 (58.7%) women, 1167 (39.6%) hypertensive patients, 269 (9.1%) diabetic patients, and 736 (25.0%) patients with IR. In simple and multivariate‐adjusted regression analyses, serum lnNTproBNP were both negatively associated with HOMA‐IR (β = −0.19 to −0.25; p < 0.0001). Similar results were also obtained in multiple subgroup analyses. In multiple logistic regression analyses, elevated serum NT‐proBNP was associated with lower risks of IR (odds ratios: 0.68 and 0.39; 95% confidence intervals: 0.61–0.74 and 0.30–0.50 for lnNTproBNP and top vs. bottom tertiles, respectively; p < 0.0001). In conclusion, increased serum NT‐proBNP level was strongly associated with a lower risk of IR in Chinese.

Objective We conducted meta-analysis of relevant case-control trials to determine the association between endothelial nitric oxide synthase (eNOS) intron 4a/b gene polymorphisms and hypertension susceptibility. Methods We searched the PubMed, Cochrane, and Embase databases using relevant keywords and reviewed pertinent literature sources. All articles published up to July 2019 were considered for inclusion. Based on the qualified studies, we performed a meta-analysis of the associations between eNOS intron 4a/b polymorphisms and the risk of hypertension. Results Fourteen studies were included in this meta-analysis, including 3344 cases and 3377 controls. The eNOS intron 4a/b locus was significantly associated with increased susceptibility to hypertension (including essential hypertension) in the overall population, according to dominant, allelic, homozygote, heterozygote, and regressive models, in the mixed population according to the regressive model, and in Caucasians according to the dominant, allelic, heterozygote, and regressive models. The eNOS intron 4a/b locus was also significantly associated with increased susceptibility to essential hypertension in the mixed population according to the heterozygote model. Conclusion eNOS intron 4a/b gene polymorphisms increase susceptibility to hypertension, including essential hypertension.

Myocardial ischemia-reperfusion injury (MIRI) is a common pathological and physiological phenomenon. Tetramethylpyrazine is the extract of the traditional Chinese medicine Chuanxiong, which can exert protective effects on MIRI in multiple ways. This paper reviewed the current research progress and evidence about the cardiovascular effects of tetramethylpyrazine, which included protecting mitochondria and improving energy metabolism, scavenging oxygen free radicals (OFRs) to inhibit lipid peroxidation, attenuating calcium (Ca2+) overload and maintaining Ca2+ homeostasis in cells, inhibiting apoptosis and protecting myocardial cells, interfering with the inflammatory reaction and mitigating cell injury, interfering with cell signaling pathways, and improving function of endothelial cells and protecting myocardial cells. However, further rigorously designed randomized controlled trials are warranted.

Sodium tanshinone IIA sulfonate (STS) injection, the extractive of traditional Chinese medicine Danshen, is supposed to be a supplementary treatment in hypertensive nephropathy. To evaluate the efficacy and safety of STS in treatment of hypertensive nephropathy. We systematically searched China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wan-fang database, Chinese Biomedicine Database (CBM), PubMed, Embase, Web of Science, and Cochrane Library from their inception to December 2018. All studies were screened by two reviewers according to the inclusion and exclusion criteria independently. The Cochrane Collaboration's risk tool was used to assess the methodological quality of the included studies. Reviewer Manager 5.3 was employed for statistical analysis. Sixteen trials involving 1,696 patients were included. The meta-analysis results indicated a combination of STS and angiotensin receptor blockers (ARBs) was more effective than ARB monotherapy in modulating hypertensive nephropathy, as represented by improved estimated glomerular filtration rate (eGFR) [mean difference (MD) = 6.87, 95% CI (4.47, 9.28), < 0.00001] and reduced 24 h urinary protein [MD = -0.23, 95% CI (-0.27, -0.19), < 0.00001], serum creatinine (SCr) [MD = -21.74, 95% CI (-24.11, -19.38), < 0.00001], cystatin-C [MD = -0.16, 95% CI (-0.24, -0.07), = 0.0003], urinary immunoglobulin G (IgG) [MD = -0.85, 95% CI (-1.11, -0.59), < 0.00001], and urinary transferrin [MD = -0.61, 95% CI (-1.04, -0.17), = 0.007]. In addition, the combination therapy had better control in systolic blood pressure (SBP) [MD = -6.53, 95% CI (-8.19, -4.87), < 0.00001] and diastolic blood pressure (DBP) [MD = -4.14, 95% CI (-5.69, -2.59), < 0.00001]. Only three trials reported adverse events, and no adverse drug reactions were observed. STS combined with ARBs had a stronger effect on improving renal function in patients with primary hypertensive nephropathy than ARB monotherapy. The combination therapy also provided auxiliary hypotensive effects. Further large-scale, multicenter, and rigorously designed randomized controlled trials (RCTs) should be conducted to confirm our findings.

Breviscapine (Dengzhanhua) injection has been wildly used in clinical treatment for cerebral infarction, cardiovascular disease, diabetic nephropathy, renal impairment of essential hypertension and stroke in China. Breviscapine injection and antihypertensive drugs combination therapy is supposed to be beneficial for hypertension-induced renal damage patients. To evaluate the beneficial and adverse effects of breviscapine injection on hypertension in hypertension-induced renal damage patients, an extensive meta-analysis was performed. We searched PubMed, the Cochrane Library, Embase, CNKI, Sino Med, VIP, and Wanfang Data for relevant literature. The timeframe of retrieval was set from the founding date of each database to September 28, 2018. Fourteen papers were included in this study. The quality of all the studies included was determined to be low. All studies were conducted with Chinese populations. Meta-analysis showed that, compared with single-use antihypertensive drugs, using breviscapine injection in combination with antihypertensive drugs to treat hypertension in hypertension-induced renal damage patients can reduce 24-h urinary total protein (24 h UTP) [WMD = -0.04, 95% CI (-0.05, -0.02), ≤ 0.001], but does not lower systolic blood pressure (SBP) [WMD = -1.02, 95% CI (-2.88, 0.84), = 0.281] or diastolic blood pressure (DBP) [WMD = -0.21, 95% CI (-1.71, 1.29), = 0.786] more effectively. There was also no statistically significant difference in adverse events between experimental groups and control groups. Breviscapine injection, in combination with antihypertensive drugs, appears to be more effective in improving the 24 h UTP, but overall have no effect on improving the blood pressure in hypertension-induced renal damage patients. Moderate dose of breviscapine injection (10 ml) may have effects on reducing blood pressure in hypertension-induced renal damage patients but high doses of breviscapine injection (20 ml) may increase blood pressure by subgroup analysis. However, the evidence of methodological quality and sample sizes is weak, and thus, further standardized research is required.

Background: Myocardial ischemia/reperfusion (I/R) injury is associated with multiple serious clinical manifestations. Autophagy is upregulated in a short period of ischemia and further enhanced during reperfusion phase, which was considered as a “double-edged sword” in the pathological process of myocardial I/R injury. In addition, NLRP3 inflammasome triggers myocardial inflammatory response, which leads to cardiomyocyte death via pyroptosis and promotes subsequent myocardial remodelling. Qishen Yiqi Dripping Pill (QSYQ) has been recognized as a potential protective agent of cardiovascular diseases. Objective: We predicted the bioactive compounds, targets and pathways of OSYQ intervening on myocardial I/R injury by network pharmacology. Furthermore, we investigated the effect of QSYQ on myocardial I/R injury and explored its underlying mechanism via autophagy and NLRP3 Inflammasome. Methods: Bioactive compounds, targets of QSYQ and relevant targets of myocardial I/R injury were collected from public databases. The protein-protein interaction network, Gene ontology and KEGG pathway enrichment analysis were carried out to screen the key compounds, target genes, functional annotation and pivotal pathways. Molecular docking was used to validate the binding association between target genes and key bioactive ingredients. Furthermore, sixty SD rats were randomized into four groups: 1) sham, 2) model, 3) captopril and 4) QSYQ pretreatment (14 days before and after surgery). Each arm was subjected to ischemia/reperfusion surgery except sham arm (30 min coronary ligation, then reperfusion). Left ventricular (LV) function were evaluated and the hearts were used to evaluate size of myocardial infarction, cardiomyocyte fibrosis, and myocardial autophagosomes. Results: The network pharmacology revealed the mechanism of QSYQ intervening on myocardial I/R injury might be related to NOD-like receptor signaling pathway, PI3K-Akt signaling pathway, autophagy-animal, etc., Molecular-docking suggested the core target proteins had good binding association with bioactive compounds of QSYQ. The experiment confirmed that QSYQ attenuated myocardial infarct size, decreased inflammatory infiltration and collagen fiber deposition and alleviated the autophagosome and myocardium ultrastructure injury, leading to LV systolic function improvement. The possible mechanism of cardioprotection was due to regulating autophagy-related proteins, activating PI3K/Akt-mTOR signaling pathway, and inhibiting activation and assembly of NLRP3 inflammasome. Conclusion: QSYQ ameliorated myocardial I/R injury via suppressing excessive autophagy and NLRP3 Inflammasome.

Protection against hypoxia injury is an important therapeutic strategy for treating hypertensive nephropathy. In this study, the effects of Qian Yang Yu Yin granule (QYYY) on spontaneously hypertensive rats fed with high salt diet and HEK293T cells exposed to hypoxia were investigated. After eight weeks’ treatment of QYYY, blood pressure, serum creatinine, serum cystatin C, blood urea nitrogen, urinary β2-microglobulin, urinary N-acetyl-β-glucosaminidase, and urinary microalbumin were assessed. The changes of hypoxia-inducible factor-1α (HIF-1α), pyruvate kinase M2 (PKM2), glucose transport 1 (GLUT1), lactate dehydrogenase A (LDH-A), connective tissue growth factor (CTGF), transforming growth factor-β1 (TGF-β1), ATP, lactate, pyruvate, and pathology were also assessed in vivo . HEK293T cells pre-treated with QYYY and/or HIF-1α over expressing cells were cultured in a three gas hypoxic incubator chamber (5% CO 2 , 1% O 2 , 94% N 2 ) for 12 h and then the expressions of HIF-1α, PKM2, GLUT1, LDH-A, CTGF, TGF-β1, ATP, lactate, and pyruvate were detected. Our results showed that QYYY promoted the indicators of renal inflammation and fibrosis mediated by HIF-1α/PKM2 positive feedback loop in vivo and vitro . Our findings indicated that QYYY treated hypertensive nephropathy by regulating metabolic reprogramming mediated by HIF-1α/PKM2 positive feedback loop.

Danhong Injection (DHI) has been widely used to treat various diseases in China for many years. The objective of this systematic review was to evaluate the efficacy of DHI combined with antihypertensive drugs for treatment of hypertensive nephropathy. Seven databases were searched from inception to September 21st, 2019. Randomized controlled trials comparing DHI combined with antihypertensive drugs antihypertensive drugs alone were extracted. The primary outcome was microalbuminuria (mALB). Secondary outcomes included systolic blood pressure (SBP), diastolic blood pressure (DBP), and serum creatinine (SCr). Fifteen studies were included in the meta-analysis, which indicated that DHI combined with antihypertensive drugs has advantages compared with antihypertensive drugs alone for reducing mALB [weighted mean difference (WMD) = -12.86, 95% confidence interval (CI) (-14.72, -11.0), < 0.01], lowering SBP [WMD = -2.84, 95% CI (-4.56, -1.12), = 0.001] and DBP [WMD = -2.38, 95% CI (-4.34, -0.43), P = 0.017], and decreasing SCr [WMD = -40.45, 95% CI (-55.69, -25.21), P < 0.01]. The combination of DHI with antihypertensive drugs appears to be more effective than antihypertensive drugs alone for treatment of hypertensive nephropathy. A moderate duration (≤4 weeks) of DHI administration is reasonable, and longer treatment with DHI should be avoided, according to the results of subgroup analysis.

Background: Hypertensive cerebral small vessel disease (HT-CSVD) is a cerebrovascular clinical, imaging and pathological syndrome caused by hypertension (HT). The condition manifests with lesions in various vessels including intracranial small/arterioles, capillaries, and small/venules. Hypertensive cerebral small vessel disease has complex and diverse clinical manifestations. For instance, it can present as an acute stroke which progresses to cause cognitive decline, affective disorder, unstable gait, dysphagia, or abnormal urination. Moreover, hypertensive cerebral small vessel disease causes 25–30% of all cases of ischemic strokes and more than 50% of all cases of single or mixed dementias. The 1-year recurrence rate of stroke in cerebral small vessel disease patients with hypertension is 14%. In the early stage of development, the symptoms of hypertensive cerebral small vessel disease are concealed and often ignored by patients and even clinicians. Patients with an advanced hypertensive cerebral small vessel disease manifest with severe physical and mental dysfunction. Therefore, this condition has a substantial economic burden on affected families and society. Naotaifang (NTF) is potentially effective in improving microcirculation and neurofunction in patients with ischemic stroke. In this regard, this multicenter randomized controlled trial (RCT) aims to furtherly evaluate the efficacy and safety of naotaifang capsules on hypertensive cerebral small vessel disease. Methods: This study is a multicenter, randomized, double-blind, placebo-controlled clinical trial. A total of 388 eligible subjects were recruited from the First Hospital of Hunan University of Chinese Medicine, Hunan Academy of Chinese Medicine Affiliated Hospital, the First Hospital of Shaoyang University, the First Traditional Chinese Medicine Hospital of Changde, and Jiangmen Wuyi Hospital of Traditional Chinese Medicine from July 2020 to April 2022. After a 4-week run-in period, all participants were divided into the intervention group (represented by Y-T, N-T) and control group (represented by Y-C, N-C); using a stratified block randomized method based on the presence or absence of brain damage symptoms in hypertensive cerebral small vessel disease (represented by Y and N). The Y-T and N-T groups were administered different doses of naotaifang capsules, whereas Y-C and N-C groups received placebo treatment. These four groups received the treatments for 6 months. The primary outcome included Fazekas scores and dilated Virchow-robin spaces (dVRS) grades on magnetic resonance imaging (MRI). The secondary outcomes included the number of lacunar infarctions (LI) and cerebral microbleeds (CMB) on magnetic resonance imaging, clinical blood pressure (BP) level, traditional Chinese medicine (TCM) syndrome scores, mini-mental state examination (MMSE) scale, and safety outcomes. Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds on magnetic resonance imaging were tested before enrollment and after 6 months of treatment. The clinical blood pressure level, traditional Chinese medicine syndrome scores, mini-mental state examination scale and safety outcomes were tested before enrollment, after 3-month, 6-month treatment and 12th-month follow-up respectively. Conclusion: The protocol will comfirm whether naotaifang capsules reduce Fazekas scores, dilated Virchow-robin spaces grades, and the number of lacunar infarctions and cerebral microbleeds, clinical blood pressure, increase mini-mental state examination scores, traditional Chinese medicine syndrome scores of Qi deficiency and blood stasis (QDBS), and improve the quality of life of subjects. The consolidated evidence from this study will shed light on the benefits of Chinese herbs for hypertensive cerebral small vessel disease, such as nourishing qi, promoting blood circulation and removing blood stasis, and dredging collaterals. However, additional clinical trials with large samples and long intervention periods will be required for in-depth research. Clinical Trial registration: www.chictr.org.cn , identifier ChiCTR1900024524.

BackgroundNonalcoholic fatty liver disease (NAFLD) is a leading public health problem worldwide. Approximately one fourth of patients with nonalcoholic fatty liver (NAFL) progress to nonalcoholic steatohepatitis (NASH), an advanced stage of NAFLD. Hence, there is an urgent need to make a better understanding of NAFLD heterogeneity and facilitate personalized management of high-risk NAFLD patients who may benefit from more intensive surveillance and preventive intervene.MethodsIn this study, a series of bioinformatic methods were performed to identify NAFLD progression-specific pathways and genes, and three machine learning approaches were combined to construct a risk-stratification gene signature to quantify risk assessment. In addition, bulk RNA-seq, single-cell RNA-seq (scRNA-seq) transcriptome profiling data and whole-exome sequencing (WES) data were comprehensively analyzed to reveal the genomic alterations and altered pathways between distinct molecular subtypes.ResultsTwo distinct subtypes of NAFL were identified with the NAFLD progression-specific genes, and one subtype has a high similarity of the inflammatory pattern and fibrotic potential with NASH. The established risk-stratification gene signature could discriminate advanced samples from overall NAFLD. COL1A2, one key gene closely related to NAFLD progression, is specifically expressed in fibroblasts involved in hepatocellular carcinoma (HCC), and significantly correlated with EMT and angiogenesis in pan-cancer. Moreover, the β-catenin/COL1A2 axis might play a critical role in fibrosis severity and inflammatory response during NAFLD-HCC progression.ConclusionIn summary, our study provided evidence for the necessity of molecular classification and established a risk-stratification gene signature to quantify risk assessment of NAFLD, aiming to identify different risk subsets and to guide personalized treatment.